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We investigated the possible involvement of phos-phatidylcholine-specific phospholipase C (PC-PLC) in the thyroid-stimulating hormone (TSH)-induced pro-tein kinase C (PKC)/phospholipase D (PLD) activation in FRTL-5 thyroid cells. Treatment of TSH resulted in both dose- and time-dependent increases in PLD activ-ity. TSH induced translocations of PKCa and RhoA from the cytosol to the membrane within 30 min. TSH also stimulated diacylglycerol (DAG)/phosphorylcho-line (PhoCho) production via PC-PLC. Pretreatment of the cells with D609, a potent inhibitor of PC-PLC, effectively inhibited the translocation of PKCa from the cytosol to the membrane and significantly de-creased TSH-induced PLD activation. Moreover, C3 transferase, an inhibitor of RhoA, significantly inhib-ited PLD activity that was stimulated by TSH, which suggests that RhoA is also involved in TSH-induced PLD activation. As we expected, pretreatment of the cells with both C3 transferase and D609 completely inhibited the TSH-induced PLD activity. These find-ings suggest that DAG that is produced from cellular PC through PC-PLC plays an essential role in the TSH-induced PKC/PLD activation. Also, RhoA and PKCa are involved in the regulation of TSH-induced PLD activation in FRTL-5 thyroid cells.